Compounds useful for treating neurological disorders

ABSTRACT

The invention relates to the use of compounds for the preparation of a medicament for treating neuropathic pain, migraine, psychiatric disorder and/or neuronal degeneration. The invention additionally relates to a pharmaceutical composition comprising compounds for treating neuropathic pain, migraine, psychiatric disorder and/or neuronal degeneration. A method for treating neuropathic pain, migraine, psychiatric disorder and/or neuronal degeneration is also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of International Application No. PCT/IL2004/000689, filed Jul. 28, 2004, which claims priority of U.S. Provisional Application No. 60/490,273, filed Jul. 28, 2003. The entire contents of both applications being hereby incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to compounds for the treatment of neurological disorders preferably neuropathic pain, migraine, psychiatric disorders and/or neuronal degeneration.

BACKGROUND OF THE INVENTION

Neuropathic pain is an intractable pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system. Neuropathic pain is part of the neurological disease spectrum and may be an expression of severe medical pathology [Hansson P. European J. of Pain 2002; 6; 45]. Neuropathic pain manifests itself due to neurological disorders accompanying various causes such as wound, infection, cancer, ischemia and metabolic disorders including diabetes mellitus. Though there are many unclear points on the mechanism of neuropathic pain, it is considered that abnormal continuous firing of sensory nerve and the like are the cause. Typical symptoms of neuropathic pain include allodinia, hyperalgesia, hyperesthesia and the like. Their symptoms include characteristic pains expressed as “like burning”, “like stinging”, “like electrical shock” and the like. Unfortunately, and unlike other types of pain, neuropathic-pain tends to respond poorly to analgesic medication.

It is known that analgesics, particularly narcotic analgesics and the like, which are effective for general nociceptive pains are hardly effective for neuropathic pain. For example, it is known that morphine has a strong analgesic effect on nociceptive pains but does not show a sufficient effect on neuropathic pain.

Patients with neuropathic pain do not respond to non-steroidal anti-inflammatory drugs and resistance or insensitivity to opiates is common. Patients are usually treated empirically with tricyclic or serotonin and norephinephrine uptake inhibitors, and anticonvulsants that all have limited efficacy and undesirable side effects. Neurosurgical lesions have a negligible role and functional neurosurgery, including dorsal column or brain stimulation, is controversial, although transcutaneous nerve stimulation may provide some relief. Local anaesthetic blocks targeted at trigger points, peripheral nerves, plexi, dorsal roots, and the sympathetic nervous system have useful but short lived effects; longer lasting blocks by phenol injection or cryotherapy risk irreversible functional impairment and have not been tested in placebo-controlled trials. Chronic epidural administration of drugs such as clonidine, steroids, opiates, or midazolam is invasive, has side effects and the efficacy of these drugs has not been adequately assessed [Woolf J. et al. Lancet 1999; 353; 1959-64].

Valproic acid (VPA), is one of the major antiepileptic drugs used today, having a wide use in both generalized and partial epilepsies. VPA has not been well studied for effect on neuropathic pain and the role of VPA in the treatment of neuropathic pain has not been determined by clinical trials. In one double-blind placebo-controlled trial of VPA reported on so far for the treatment of neuropathic pain due to spinal cord injury there was no difference between VPA and placebo in relieving pain [Backonja M. M. The Clinical Journal of Pain, 16, S67-S72, 2000].

Additionally, the use of Valproic acid (VPA), is limited by its considerable adverse effects including hepatotoxicity and teratogenicity and thus cannot be given to women of childbearing age and children [Baille, T. A. et al. In Antiepileptic Drugs, eds. R. H. Levy et al. Raven Press, New York. Pp. 641-651 (1989)].

Since a safe and effective therapeutic method has not been established, concern has been directed toward the development of a therapy effective for neuropathic pain.

There is thus a widely recognized need for, and it would be highly advantageous to have, new agents for treating neuropathic pain devoid of the above limitations.

Valnoctamide (VCD), an amide analogue of VPA having anti-convulsant activity was found to be distinctly less teratogenic than VPA [Radatz M et al. Epilepsy Res. 1998:30(1):41-8]. M. Roeder et al [M. Roeder et al, Tetrahedron: Asymmetry 1999: 10: 841-853] and US Pat. No. 6,417,399 relate to stereoisomers of valnoctamide (VCD), synthesis thereof, a method for stereoselective separation thereof as well as uses thereof.

U.S. Pat. No. 5,880,157 and M. Bialer et al. [M. Bialer et al. Pharm Res. 13:284-289 (1996)] disclose derivatives of 2,2,3,3 tetramethylcyclopropane carboxylic acid for treating epilepsy. Isoherranen N. et al 2002, studied the anticonvulsant activity of N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite in various animal (rodent) models of human epilepsy, and evaluated their ability to induce neural tube defects (NTDs) and neurotoxicity. [Isoherranen N. et al. Epilepsia 2002; 43:115-126]. M-TMCD (a cyclopropyl analog of VPA) was found to be advantageous compared to VPA because of its better potency as an anticonvulsant drug, its wider safety of margin, its lack of teratogenicity and its potential lack of hepatotoxicity.

Thus, there is a widely recognized need and it will be highly advantageous to have compounds which are effective in treating neuropathic pain with minimal side effects. Additionally, it would be highly advantageous to have compounds effective against migraine, psychiatric disorders and/or neurodegenerative diseases.

SUMMARY OF THE INVENTION

According one aspect of the present invention there is provided use of a compound of formula [A]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl;

(iii) n is 0 or 1; and

(iv) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R^(5,) R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [A],         for the preparation of a medicament for treating a disease or         condition selected from: neuropathic pain, migraine and neuronal         degeneration; with the proviso that where the use is for the         treatment of migraine, compounds disclosed in WO 99/54282,         incorporated herein by reference in its entirety, are excluded.         Among the excluded compounds are: propylisopropyl acetic acid,         propylisopropyl acetamide, valnoctamide, valnoctic acid,         diisopropyl acetamide and diisopropyl acetic acid, in racemic         and stereoisomeric forms.

In a preferred embodiment, there is provided use of a compound of formula I

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl;     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [I],         for the preparation of a medicament for treating a disease or         condition selected from: neuropathic pain, migraine and neuronal         degeneration.

According to another aspect of the present invention there is provided use of a compound of formula [A] or [I] as defined above, for the preparation of a medicament for treating a psychiatric disorder, especially a bipolar disorder. In the case of medicaments for treating psychiatric disorders, excluded are compounds of formula II:

wherein R¹ and R² are independently selected from H and C₁-C₆ alkyl.

According to another aspect of the present invention there is provided a pharmaceutical composition for treating a disease or condition selected from: neuropathic pain, migraine, and neuronal degeneration comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound of formula [A]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl;

(iii) n is 0 or 1; and

(iv) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R^(5,) R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,         including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [A], with the proviso that         where the use is for the treatment of migraine, compounds         disclosed in WO 99/54282, incorporated herein by reference in         its entirety, are excluded. Among the excluded compounds are:         propylisopropyl acetic acid, propylisopropyl acetamide,         valnoctamide, valnoctic acid, diisopropyl acetamide and         diisopropyl acetic acid, in racemic and stereoisomeric forms.

In a preferred embodiment, there is provided a pharmaceutical composition for treating a disease or condition selected from: neuropathic pain, migraine and neuronal degeneration comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound of formula [I]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [I].

According to another aspect of the present invention there is provided a pharmaceutical composition for treating a psychiatric disorder, comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound of formula [A] or [I] as defined above. Excluded from the above formulae are compounds of formula II:

wherein R¹ and R² are independently selected from H and C₁-C₆ alkyl.

According to yet another aspect of the present invention there is provided a method for treating a disease or condition selected from: neuropathic pain, migraine and neuronal degeneration, in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula [A]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl;

(iii) n is 0 or 1;and

(iv) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [A], with the proviso that         where the method is for the treatment of migraine, compounds         disclosed in WO 99/54282, incorporated herein by reference in         its entirety, are excluded. Among the excluded compounds are:         propylisopropyl acetic acid, propylisopropyl acetamide,         valnoctamide, valnoctic acid, diisopropyl acetamide and         diisopropyl acetic acid, in racemic and stereoisomeric forms.

In a preferred embodiment, there is provided a method for treating a disease or condition selected from: neuropathic pain, migraine and neuronal degeneration, in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula [I]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R^(3,) R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [I].

According to yet another aspect of the present invention there is provided a method for treating a psychiatric disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula [A] or [I] as defined above. Excluded from the above formulae are compounds of formula II:

wherein R¹ and R² are independently selected from H and C₁-C₆ alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of a compound of formula I

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R^(1,) R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R^(5,) R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl;     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [I],         for the preparation of a medicament for treating a disease or         condition selected from: neuropathic pain, migraine and neuronal         degeneration, with the proviso that where the use is for the         treatment migraine, compounds disclosed in WO 99/54282,         incorporated herein by reference in its entirety, are excluded.         Among the excluded compounds are: valnoctamide, valnoctic acid,         diisopropyl acetamide and diisopropyl acetic acid, in racemic         and stereoisomeric forms.

The present invention additionally relates to the use of a compound of formula [A]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl;

(iii) n is 0 or 1; and

(iv) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [A],         for the preparation of a medicament for treating a disease or         condition selected from: neuropathic pain, migraine and neuronal         degeneration, with the proviso that where the use is for the         treatment migraine, compounds disclosed in WO 99/54282,         incorporated herein by reference in its entirety, are excluded.         Among the excluded compounds are: propylisopropyl acetic acid,         propylisopropyl acetamide, valnoctamide, valnoctic acid,         diisopropyl acetamide and diisopropyl acetic acid, in racemic         and stereoisomeric forms.

The present invention additionally relates to a method for treating a disease or condition selected from: neuropathic pain, migraine and neuronal degeneration, in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula I

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [I], with the proviso that         where the method is for the treatment migraine, compounds         disclosed in WO 99/54282, incorporated herein by reference in         its entirety, are excluded. Among the excluded compounds are:         valnoctamide, valnoctic acid, diisopropyl acetamide and         diisopropyl acetic acid, in racemic and stereoisomeric forms.

The present invention additionally relates to a method for treating a disease or condition selected from: neuropathic pain, migraine and neuronal degeneration, in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula [A]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl;

(iii) n is 0 or 1;and

(iv) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [A], with the proviso that         where the method is for the treatment migraine, compounds         disclosed in WO 99/54282, incorporated herein by reference in         its entirety, are excluded. Among the excluded compounds are:         propylisopropyl acetic acid, propylisopropyl acetamide,         valnoctamide, valnoctic acid, diisopropyl acetamide and         diisopropyl acetic acid, in racemic and stereoisomeric forms.

The present invention also relates to a method for treating a psychiatric disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula [A] or [I] as defined above. Excluded from the above formulae are compounds of formula II:

It should be noted that the present invention also excludes the compound valproic acid for all the indications mentioned above.

As used herein the term “the other of R³, R^(4,) R⁵ and R⁶” refers to the two groups of R³, R⁴, R⁵ and R⁶ which do not form a cyclopropyl ring. For example, when R³ and R⁵ form together a cyclopropyl ring “the other . . . ” is R⁴ and R⁶. When R⁴ and R⁵ form together a cyclopropyl ring “the other . . . ” is R³ and R⁶, etc.

As used herein the term “treating” includes prophylactic and/or therapeutic uses and refers to abrogating, preventing, alleviating, slowing or reversing the progression of a disease or condition, or substantially preventing the appearance of clinical symptoms of a disease or condition.

As used herein the term “neuropathic pain” refers to any pain which initial cause was due to damage, or injury to the neural tissue. The predominant mechanism is aberrant somatosensory processing.

As used herein the term “neuronal degeneration” refers to a condition of neuronal death or decrease in neuronal function (such as decrease in neurotransmitter release). The degeneration may be due to a neurodegenerative disease (such as Alzheimer's disease. Parkinson, Huntignton Chorea etc.), due to trauma such as that following head injury or operation, due to lack ischemia or hypoxia following trauma, stroke or a disease process, or due to natural degenerative processes caused by old age.

As used herein the term “migraine” refers to an often familial symptom complex of periodic attacks of vascular headache, usually temporal and unilateral in onset, commonly associated with irritability, nausea, vomiting, constipation or diarrhoea and often photophobia, attacks are preceded by constriction of the cranial arteries, usually with resultant prodromal sensory (especially ocular) symptoms and commence with the vasodilation that follows.

As used herein the term “psychiatric disorder” refers especially to bi-polar disorder or manic-depressive illness, affective disorder and generalized anxiety disorder (GAD).

The medicaments of the present invention may be useful as anxiolytic and/or mood stabilizers.

As used herein the term “therapeutically effective amount” refers to an amount of a compound sufficient to prevent, inhibit, reduce, or eliminate one or more causes, symptoms, or complications of neuropathic pain, migraine, psychiatric disorder and/or neuronal degeneration.

The term “therapeutically effective amount” also refers to an amount of a compound sufficient to bring about at least one of the effects defined under the term treating.

Preferably the C₁-C₆ alkyl of R¹ and R² consists of 1-3 carbon atoms and most preferably the alkyl is a methyl.

Preferably the C₁-C₆ alkyl of R³, R⁴, R⁵ and R⁶ consists of 1-3 carbon atoms, more preferably 1-2 carbon atoms and most preferably the alkyl is a methyl.

As used herein the term “C₁-C₆alkyl” refers to a saturated aliphatic hydrocarbon of 1 to 6 carbon atoms. In case the alkyl includes 2-6 carbon atoms, the alkyl may have one or more carbon-carbon double bonds (termed also alkenyl). Thus, R³, R⁴, R⁵ and R⁶ may also be an alkenyl (an unsaturated straight or branched aliphatic hydrocarbon, having one or more carbon-carbon double bonds) including 2 to 6 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, n-propenyl, isopropenyl etc.

Whenever a numerical range e.g. “1-6” is stated herein, it means that the group in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms. The C₁-C₆alkyl group may be for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, sec-butyl, amyl, pentyl, isopentyl, or hexyl.

The C₁-C₆ alkyl group may be a straight or a branched alkyl group.

Preferably the total number of carbon atoms of R³, R⁴, R⁵ and R⁶ in a compound of formula I is two. The term “the total number of carbon atoms of R³, R⁴, R⁵ and R⁶” means the sum of carbon atoms of R³, R⁴, R⁵ and R⁶.

Preferably the total number of carbon atoms in a compound of formula I (or of formula A) excluding the carbon atoms of R¹ and R² is eight.

According to a preferred embodiment of the present invention,

(i) X is OH; and

(ii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl.

According to another preferred embodiment of the present invention,

(i) X is NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl.

Additionally according to a preferred embodiment of the present invention,

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H, methyl and ethyl; R⁵, R⁶ are independently selected from H, methyl and ethyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H, methyl and ethyl.

Moreover according to a more preferred embodiment of the present invention,

X is selected from OH and NR¹R²; R, R² are independently selected from H and C₁-C₆ alkyl; and one of R³ and R⁴, together with one of R⁵ and R⁶, form a cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is a methyl.

Further according to a more preferred embodiment the compound of formula I or [A] is of structural formula II

wherein R¹ and R² are independently selected from H and C₁-C₆ alkyl.

According to this preferred embodiment and with relation to formula [I], X is NR¹R²; R¹, R² are independently selected from H and C₁-C₆ alkyl; and one of R³ and R⁴, together with one of R⁵ and R⁶, form a cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is a methyl.

Preferably the C₁-C₆ alkyl is a C₁-C₃ alkyl and most preferably a methyl.

Preferably at least one of R¹ and R² is H and the other of R¹ and R² is a C₁-C₆ alkyl.

As used herein the term “the other of R¹ and R²” refers to the non-hydrogen group. For example, if R¹ is H, then R² is C₁-C₆ alkyl and vice versa.

Preferably the C₁-C₆ alkyl of R¹ and R² is a C₁-C₃ alkyl and most preferably a methyl.

According to a preferred embodiment of the present invention one of R¹ and R² is H and the other of R¹ and R² is C₁-C₆ alkyl, more preferably C₁-C₃ alkyl and most preferably methyl.

According to another preferred embodiment of the present invention R¹ and R² are H.

Preferred compounds are the following:

N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (M-TMCD)—compound III;

2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD)—compound IV;

2-ethyl-3-methyl-pentanoic acid amide (Valnoctamide)—compound V, for treating neuropathic pain and neuronal degeneration;

propyl isopropylacetamide (PID)—compound VI, for treating neuropathic pain and neuronal degeneration;

diisopropylacetamide (DID)—compound VII, for treating neuropathic pain and neuronal degeneration; and

diisopropylacetic acid (DIA)—compound VIII, for treating neuropathic pain and neuronal degeneration,

where applicable as racemic mixtures or as individual stereoisomers (i.e. where the compound contains at least one asymmetric carbon atom) and when applicable, including pharmaceutically acceptable salts, hydrates and solvates of each compound (i.e. if the chemical structure affords the formation of salts, hydrates or solvates) from the list of compounds below.

More preferred compounds are N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (M-TMCD), diisopropylacetamide (DID), propyl isopropylacetamide (PID) in racemic form or 2R and 2S stereoisomeric form and 2-ethyl-3-methyl-pentanoic acid amide (Valnoctamide) in racemic or stereoisomeric form and most preferred compound is N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (M-TMCD). List of Compounds:

For purposes of this specification, the term VCD refers to 2-ethyl-3-methyl-pentanoic acid amide (Valnoctamide).

Additional preferred compounds are: 2-ethyl-3-methyl-pentanoic acid (valnoctic acid (VCA)), for treating neuropathic pain and neuronal degeneration; and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA).

When X is OH; and one of R³ and R⁴, together with one of R⁵ and R⁶, form a cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is a methyl, the compound is TMCA.

The compound may also be propylisopropyl acetic acid (PIA), for treating neuropathic pain and neuronal degeneration.

According to a preferred embodiment of the present invention the disease or condition is a neuropathic pain.

Preferably the psychiatric disorder is a bipolar disorder.

Preferably the psychiatric disorder is a bipolar disorder and the compound is selected from PID, PIA, VCD, VCA, DID, and DIA.

Preferably the compound is administered as a pharmaceutical composition comprising a compound of formula I or [A] and a pharmaceutical acceptable carrier.

According to a preferred embodiment of the present invention the route of administration of the medicament is selected from oral, parenteral, topical, transdermal, mucosal, rectal and buccal administration.

According to a preferred embodiment of the present invention the route of administration of the compound is selected from oral, parenteral, topical, transdermal, mucosal, rectal and buccal administration.

More preferably the route of administration of the medicament is selected from oral and parenteral administration and most preferably oral administration.

More preferably the route of administration of the compound is selected from oral and parenteral administration and most preferably oral administration.

Preferably the parenteral route of administration is selected from intravenous, intramuscular, intraperitoneal and subcutaneous administration.

Preferably the mammal is a human.

The invention further relates to a pharmaceutical composition for treating a disease or condition selected from: neuropathic pain, migraine, and neuronal degeneration comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound of formula [A] as defined above.

Preferably, the invention relates to a pharmaceutical composition for treating a disease or condition selected from: neuropathic pain, migraine, and neuronal degeneration comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound of formula [I]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein

(i) X is selected from OH and NR¹R²;

(ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and

(iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or

-   -   (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a         cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected         from H and C₁-C₆ alkyl,     -   including pharmaceutically acceptable salts, hydrates and         solvates of the compound of formula [I].

The invention also relates to a pharmaceutical composition for treating a psychiatric disorder, with the exclusion of compounds of formula [II] as defined above.

The pharmaceutical compositions of the present invention comprises as an active ingredient a therapeutically effective amount of at least one compound as described in the present invention and a pharmaceutically acceptable carrier.

As used herein a “pharmaceutical composition” refers to a preparation of one or more compounds described herein, with other inert chemical components such as suitable pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject (mammal).

As used herein the term “pharmaceutically acceptable carrier” refers to an inert non-toxic carrier or diluent that does not cause significant irritation to a subject (mammal) and does not abrogate the biological activity and properties of the administered compound.

Examples without limitation of carriers are lactose, sucrose, water, organic solvents and polyethyleneglycol.

The carriers may include additional excipients such as binders, disintegrants, lubricants, surface active agents, preservatives and favoring agents.

The treatment may be prophylactic, for preventing the disease from occurring such as for preventing neuropathic pain following surgery by administration of the compound of the invention prior to surgery. Alternatively the administration may be performed after the disease or condition were already established so as to eliminate or decrease at least one of the manifestations of the disease or condition.

Preferably the disease is neuropathic pain, and the compound may be administered to prevent the occurrence of the pain (for example before amputation surgery, to a diabetic patient likely to develop diabetic neuropathy) or may be administered after the neuropathic pain is already established so as to eliminate or reduce the intensity of the pain as compared to the non-treated condition.

Modes of Administration and Amounts

The method of administration of the compounds above may be oral, parenteral, topical, transdermal, mucosal or buccal. The pharmaceutical composition may also be administered rectally for example through the use of an enema or suppository. The term “mucosal” refers to a tissue comprising a mucous membranes, such as the nasal mucosa, pulmonary mucosa, oral mucosa (such as sublingual or buccal) or rectal mucosa. Compositions for administration through the mucosal route include for example nasal spray or nasal drops or aerosol for inhalation.

In the practice of the invention the amount of the compound incorporated in the pharmaceutical composition and the dosage may vary widely. Factors considered when determining the precise dosage are well known to those skilled in the art. Examples of such factors include, but are not limited to, age, sex and weight of the subject being treated, intended medical use of the compounds, severity of the disease, patient's general condition, the dosage form, route of administration being employed and the frequency with which the composition is to be administered.

Most preferably, the pharmaceutical composition is in the form of an oral preparation.

Because of their ease of administration, tablets and capsules are preferred and represent the most advantageous oral dosage unit form, in which case solid pharmaceutical excipients are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.

Preferably, the oral pharmaceutical compositions of the present invention may be administered in single or divided doses, from one to four times a day. The oral dosage—forms may be conveniently presented in unit dosage forms and prepared by any methods well known manner the art of pharmacy. Preferably, the therapeutically or prophylactically effective amount of an active ingredient ranges from about 20 mg to about 1000 mg daily (preferably administered orally), more preferably from about 50 mg to about 500 mg daily, and most preferably from about 100 mg to about 400 mg daily (preferably administered orally). The daily dose may be administered either singly or in multiple dosage over 24-hour period. For oral administration, the therapeutically effective amount of the active ingredient may be several times greater than that for, parenteral administration. The amount of the orally administered active ingredient may range from about five to ten times greater than that for intravenous or subcutaneous administration.

Pharmaceutical Compositions and Dosage Forms Useful in the Invention

Pharmaceutical compositions and dosage forms which may be used in the invention comprise one or more of the active ingredients disclosed herein. Pharmaceutical compositions and dosage forms of the invention typically also comprise one or more pharmaceutically acceptable excipients or diluents (pharmaceutical acceptable carrier).

Single unit dosage forms of the invention are suitable for example for oral, mucosal (e.g., nasal, sublingual, buccal, pulmonary, or rectal mucosa), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, intraarterial, intraperitoneal or subcutaneous), or transdermal administration to a patient.

Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

Oral Dosage Forms Pharmaceutical Compositions

Oral dosage forms of the present invention suitable for oral administration may be presented as discrete pharmaceutical unit dosage forms, such as capsules, soft elastic gelatin capsules, tablets, caplets, cachets, or aerosols sprays, each containing a predetermined amount of the active ingredients, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Dosage forms such as oil-in-water emulsions typically comprise surfactants such as an anionic surfactant, for example anionic phosphate ester or lauryl sulfates, but other types of surfactants such as cationic or nonionic surfactants may be used in the compositions of the present invention. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Pharmaceutical compositions of the present invention suitable for oral administration may be formulated as a pharmaceutical composition in a soft elastic gelatin capsule unit dosage form by using conventional methods well known in the art. See, e.g., Ebert, Pharm. Tech, 1(5):44-50 (1977). Pharmaceutical compositions in the form of capsules or tablets coated by an entero-soluble gastroresistant film and which contains a lyophilisate consisting of glycosaminoglyean, a thickening agent, and a surfactant have been previously described in U.S. Pat. No. 5,252,339, which is incorporated herein by reference in its entirety. Soft elastic gelatin capsules have a soft, globular gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol. The hardness of the capsule shell may be changed by varying the type of gelatin used and the amounts of plasticizer and water.

Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Preparation of the Compounds

The compounds of the present invention can be prepared according to the methods disclosed in Sterling et al (U.S. Pat. No. 5,880,157), M. Bialer et al, Pharm Res. 13:284-289 (1996) and Freifelder et al. J. Org. Chem. 26:203 (1961) or a modification thereof which will be apparent to those skilled in the art. The disclosures of these references are incorporated herein by reference in their entirety.

M-TMCD and TMCD were prepared according to the method disclosed in Sterling et al (U.S. Pat. No. 5,880,157). Valnoctamide (VCD, powder) was given as a gift from Sanofi, France. VCD can also be obtained from ClinMeddy (Italy). VCD steroisomers can be synthesized as disclosed in U.S. Pat. No. 6,417,399.

PID, DID and DIA were prepared as disclosed in HAJ-YEHIA, A., & BIALER, M (1989). Structure-pharmacokinetic relationship in series of valpromide isomers with entiepileptic activity. Pharm. Res., 6, 683-689; HAJ-YEHIA, A., & BIALER, M (1990). Structure-pharmacokinetic relationship in series of short fatty acid amides that possess anticonvulsant activity. J. Pharm. Sci., 79, 719-724.

PID stereoisomers can be prepared as disclosed in SPIEGELSTEIN O. et al (1999) Enantioselective synthesis and teratogenicity of propylisopropyl acetamide, a CNS active chiral amide analogue of valproic acid. Chirality, 1, 645-650.

TMCD can be prepared as disclosed in BIALER M. et al. (1996) Pharmacokinetic analysis and antiepileptic activity of Tetra-Methylcyclopropane analogeous of valpromide. Pharm. Res. 13, 284-289.

The disclosures of the above references are incorporated herein by reference in their entirety.

2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) can be obtained from Sigma Aldrich.

BREIF DESCRIPTION OF THE DRAWING

FIG. 1. Shows the threshold of mechanical sensitivity of the rat foot as a function of time after administration of M-TMCD, for five different concentrations of the drug (20, 40, 60, 80, 100 mg/kg) and for methyl cellulose control (4 ml/kg). The term “B. line” refers to baseline.

FIG. 2. Shows the threshold of mechanical sensitivity of the rat foot as a function of time after administration of VCD, for five different concentrations of the drug (20, 40, 60, 80, 100 mg/kg) and for methylcellulose control (4 ml/kg). The term “B. line” refers to baseline.

FIG. 3. Shows the threshold of mechanical sensitivity of the rat foot as a function of time after administration of TMCD, for four different concentrations of the drug (40, 80, 100, 150 mg/kg) and for methylcellulose control (4 ml/kg). The term “B. line” refers to baseline.

FIG. 4. Shows the threshold of mechanical sensitivity of the rat foot as a function of time after administration of VPA, for four different concentrations of the drug (200, 250, 300, 400 mg/kg) and for methylcellulose control (4 ml/kg). The term “B. line” refers to baseline.

FIG. 5. Shows the effect of i.p. administation of PID (40 and 80 mg/kg) and vehicle (MC) on tactile allodynia in rats with SNL neuropathy. Paw withdrawal thresholds to von Frey filaments were determined on both ipsilateral and contralateral paw prior to (0) and up to 4 h after dosing, using blinded regimen. (A) Data show withdrawal threshold of individual rats for the ipsilateral paw. (B) Data show withdrawal threshold as mean value for the ipsilateral paw.

FIG. 6. Shows the effect of i.p. administration of DIA and DID on tactile allodynia in rats with SNL neuropathy. Paw withdrawal thresholds to von Frey filaments were determined on both ipsilateral and contralateral paw prior to (Pre-) and up to 4 h after dosing, using a blinded regimen. Data show withdrawal threshold as mean values for the ipsilateral paw. None of the drugs affected contralateral withdrawal thresholds. *P<0.05 compared to vehicle (MC) by nonparametric Wilcoxon one tailed test of area under the response curve 30-240 min after dosing (dose of drug tested vs. vehicle). For clarity SD errors bars are not presented.

FIG. 7. Shows PK-PD relationship. Time course of plasma concentration and antiallodynic effect following i.p. administration of DID (40 mgkg⁻¹).

FIG. 8. Plot of antiallodynic activity (SNL-ED₅₀) and anticonvulsant activity (MES-ED₅₀) in rats. The abbreviations for the various compounds are given in Table 4.

In FIGS. 1-8: *, **, *** represent the statistical significance of the dose of the compound versus methylcellulose of the same experiment. ‘*’ represent p<0.05, ‘**’ represent p<0.01 and ‘***’ represent p<0.001. MC refers to methylcellulose.

EXAMPLES

1. Experimental Procedures

A. Neuropathic Pain Model

Male Sprague-Dawley rats (Harlan laboratories, Jerusalem, Israel) weighing 200-225 g were used throughout the study. The mechanical sensitivity (tactile allodynia) of the foot was quantified by the occurrence of foot withdrawal in response to normally innocuous mechanical stimuli using nine different von Frey filaments (VFF) ranging from 0.6 to 26 g. Rats that did not withdraw the foot to mechanical stimulus (von Frey filaments) of 15 g for 2 consecutive days (−2 and −1) before surgery were included in the study. At day 0, under xylazine-ketamine anesthesia, the L5 and L6 spinal nerves of one side of the rat were tightly ligated and cut in order to induce the development of neuropathic pain syndrome as disclosed in detail in Sheen, K. and Chung, J. M., Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model, Brain Research 610: 62-68 (1993), incorporated herein by reference in its entirety. The effect on neuropathic pain (tactile allodynia) was measured 5-6 days following operation as disclosed above. Rats responding to mechanical stimuli of 10 g or less (in the operated leg) were eligible for the study and were included in the drug administration regime.

B. Surgical Procedure

The procedure of legating and cutting of the spinal nerves was performed as previously described by Sheen, K. and Chung, J. M., Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model, Brain Research 610: 62-68 (1993), incorporated herein by reference in its entirety. Briefly, under ketamine-xylazine anesthesia the rat was placed in a prone position and the left paraspinal muscles were separated from spinous processes at the L4-S2 level. Part of the L6 transverse process was removed and the L4-L6 spinal nerves were identified. The L5-L6 spinal nerves were isolated and tightly ligated and cut, distal to the dorsal root ganglion and proximal to the formation of the sciatic nerve. Following complete homeostasis the wound was sutured.

C. Drug Testing Protocol

For all the studies, appropriate amounts of compounds were suspended in a solution of 0.5% (w/v) methylcellulose in double distilled water. The 0.5% w/v methyl cellulose vehicle was prepared by dissolving 1.25 g of methyl cellulose (viscosity of 2%, 4000 centipoises, Sigma) in 250 ml of double distilled water (DDW).

A volume of 4 ml/kg (volume of injected suspension/rat body weight) was then injected to the rats. The three drugs used were, M-TMCD and VCD at concentrations of 20, 40, 60, 80 and 100 mg/kg body weight, TMCD at concentrations of 40, 80, 100 and 150 mg/kg body weight, VPA at concentrations of 200, 250, 300, 400 mg/kg and methylcellulose was used as a control at 4 ml/kg (MC, vehicle). The three drugs and the control vehicle were administered i.p. (intraperitoneally) to rats at postoperative days 7, 14 and 21 in a double blind randomized crossover manner. Tactile allodynia (response to mechanical stimulus) was challenged using VFFs of 0.6-26 g at 30 min pre-dosing (Baseline (B. line)) and at 30, 60, 120, 180 and 240 min post-dosing. Rat that obtained threshold of at least 15 g, (back to pre-operation baseline threshold), was regarded as being free of tactile allodynia. This threshold was set for the purpose of ED₅₀ determination as the inclusion criteria to this study was 15 g (considered as the minimum non-allodynic threshold).

D. Foot Withdrawal Measurements

Measurements of the foot withdrawal to normally innocuous mechanical stimuli were applied with set of 9 VFFs ranging from 0.6 g to 26 g. The rat was placed on a metal mesh floor covered with a transparent plastic dome, a period of acclimatization was allowed prior to testing. VFFs were applied from underneath the mesh floor to the plantar surface of the foot. Each trial consisted of repeated applications of each of the VFFs in an ascending order for 5 times, each for a period of 1 second. testing between two consecutive ascending VFFs was separated by period of 2 min. If the rat withdrew the foot at least 3 times out of 5 at a specific VFF no further ascending filaments were tested and this filament was considered as a withdrawal threshold (response). Mechanical stimulus trials with the series of ascending VFF were repeated 2 times for a given time point. The repeated measurements were averaged and taken as the paw withdrawal threshold on a given time point.

E. Statistical Analysis

The absolute threshold and the difference in the allodynic threshold (time point minus baseline) values were tested using Mann-Whitney Test and Kruskal-Wallis Nonparametric test (two tailed) followed by Dunn's Multiple comparison test. The ED₅₀ (median effective dose) was calculated by using Probit analysis method.

Example 1 Decrease in Neuropathic Pain Following Administration of M-TMCD.

Male Sprague-Dawley rats (Harlan laboratories, Jerusalem, Israel) weighing 200 - 225 g were used. The rats chosen feature initial lack of foot withdrawal in response to mechanical stimuli, as described in experimental A (neuropathic pain model) above. The rats underwent surgery by legating and cutting of the L5-L6 nerves, as disclosed in Experimental B (surgical procedure) above, to produce neuropathic pain as verified by tactile allodynia. Rats were divided to 3 groups including 8-10 rats per study. Each group received 2 different doses of M-TMCD i.p (selected from 20, 40, 60, 80 and 100 mg/kg) and 4 ml/kg of methyl cellulose was used as control. The doses of M-TMCD were 20, 40, 60, 80 and 100 mg/kg.

Tactile allodynia threshold was measured as base line and 30, 60, 120, 180 and 240 minutes after administration of the drug, as described in the Experimental above, the threshold being the foot withdrawal in response to mechanical stimulus trials with the series of ascending VFF.

The results are shown in FIG. 1. As can be seen, M-TMCD increased the threshold of tactile allodynia (proportional to the neuropathic pain) in a dose dependent manner, maximal increase in threshold, indicating maximal decrease in neuropathic pain was evident 60 min after administration of the drug with an ED₅₀ of 41 mg/kg.

Example 2 Decrease in Neuropathic Pain Following Administration of VCD

The same experiment described in Example 1 was repeated with VCD, and the results are shown in FIG. 2. As can be seen the rats responded in a dose dependent manner to varying dosages of VCD, with maximal effect evident 60 min after administration of the drug with an ED₅₀ of 52.3 mg/kg.

Example 3 Decrease in Neuropathic Pain Following Administration of TMCD

The same experiment described in Example 1 was repeated with TMCD, and the results are shown in FIG. 3. As can be seen the rats responded in a dose dependent manner to varying dosages of TMCD, with maximal effect evident 60 min after administration of the drug with an ED₅₀ of 84.5 mg/kg.

Example 4 Decrease in Neuropathic Pain Following Administration of Valproic Acid

The same experiment described in Example 1 was repeated with VPA (used as reference for comparison), and the results are shown in FIG. 4. As can be seen the rats responded in a dose dependent manner to varying dosages of VPA, with maximal effect evident 60 min after administration of the drug with an ED₅₀ of 269 mg/kg.

Example 5 Decrease in Neuropathic Pain Following Administration of PID

The experimental procedures are as described in Example 6.

The thresholds are shown in Table 1 and FIG. 5. Table 2 presents the number of rats protected at each time interval after PID (i.p.) administration. TABLE 1 Activity of PID as antiallodynic agents at doses of 40 and 80 mg/kg Dose (mg/kg) Time 40 80 MC  0 1.7 ± 1.3  2.6 ± 1.8 2.3 ± 1.6  30 min 3.9 ± 5.1 13.6 ± 12  2.5 ± 1.5  60 min 4.8 ± 6.3 14.0 ± 7.3 2.4 ± 1.7 120 min 6.5 ± 5.7 10.4 ± 4.8 3.1 ± 2.3 180 min 7.0 ± 8.0 13.2 ± 8.0 2.5 ± 1.3 240 min 4.0 ± 4.4  6.2 ± 3.8 1.8 ± 0.8

Data presented as mean ±SD withdrawal threshold (g) TABLE 2 Number of rats protected at each time interval after PID (i.p.) administration Dose 30 min 60 min 120 min 180 min 240 min MC 0/9 0/9 0/9 0/9 0/9 40 mg/kg 1/9 1/9 2/9 2/9 0/9 80 mg/kg 3/9 4/9 2/9 5/9 0/9

Example 6 The Effect of DID and DIA on Neuropathic Pain

Experimental Procedures

1. Materials and Methods

1. 1. Animals and Surgical Procedure

Experiments were performed on male Sprague-Dawley rats (Harlan Laboratories, Jerusalem) weighing 175-200 g. The procedure for inducing tactile allodynia in the spinal nerve ligation (SNL) model was as described by Kim & Chung (1992) (KIM, S., & CHUNG, J. M (1992). An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355-363). Briefly, under ketamine-xylazine anesthesia (85 mg kg⁻¹, i.p and 13 mg kg⁻¹, i.p, respectively) rats were placed in a prone position and paraspinal muscles on the left were separated from the L4-S2 spinous processes. Part of the L6 transverse process was removed and the underlying L4-L6 spinal nerves were identified. The L5 and L6 spinal nerves were isolated, tightly ligated with 5-0 silk, and cut just distal to the ligature. The ligature was approximately 8 mm distal to the corresponding dorsal root ganglion (DRG). Following complete homeostasis the wound was sutured in layers, the skin closed with Michel clips, topical bacteriostatic power was applied, and 20000 units of duplo-penicillin was injected intramuscularly (i.m.). After uneventful recovery, the animals were returned to the vivarium where they were maintained in groups of 2-3 in solid-bottomed 42×26 cm transparent plastic shoebox cages, bedded with pine shavings. Rat dry food pellets (Kofholk, Petah Tikva, Israel, product #19510) and water were available ad libitum. The day:night cycle was 12 h:12 h (lights on at 6 AM).

1.2. Sensory Testing

We used a set of 9 nylon von Frey monofilaments (VFF, Semmes-Weinstein monofilaments, Stoelting, Wood Dale, Ill., USA) to quantify foot withdrawal in response to normally innocuous tactile stimuli. Initial bending force of the filaments (in mN) was: 5.8, 13.4, 18.7, 37.9, 57.3, 77.5, 97.4, 145.9, and 254.1 (equivalent to mass of: 0.6, 1.4, 1.9, 3.9, 5.9, 7.9, 9.9, 14.9 and 25.9 g). Forces were calibrated by lowering filaments onto the pan of an electronic balance until they just bent. Standard deviation (SD) on repeated measurements was about ±0.2 g Filaments were cut flush, and although they did not all have the same diameter, the same set was used for all rats.

Rats were placed on a raised wire mesh screen (gaps 4 mm×4 mm), which allowed access to the plantar surface of the hindpaw from below. They were covered with a transparent plastic dome, 13 cm high, which prevented rearing on the hindlimbs. A period of 20 min was allowed for acclimation prior to sensory testing. The mid-plantar hindpaw skin just caudal to the footpads, half way between medial and lateral edges of the foot, was subjected to a series of 5 brief probes, spaced at about 1 s. Each such stimulus was sufficient to just bend the filament. Testing began with the filament with the weakest initial bending force (0.6 g). If the animal failed to respond with at least a momentary foot twitch/withdrawal to ≧3 of the 5 probes the next stiffest filament was tried, and so forth, using an ascending staircase protocol. Response threshold was the bending force of the first monofilament in the series that evoked a criterion ≧3/5 responses. This procedure was repeated twice on each foot, alternating from side to side, with ≧5 min rest between trials in a given animal. “Threshold” for each paw on a given test day was the average of the two force determinations just sufficient to evoke a criterion response. If there was no response to the stiffest filament, threshold was recorded as 26 g. Rats were included in the study only if they failed of respond to the 15 g monofilament (or weaker) on two consecutive days, two and one day before surgery.

The first postoperative tests were carried out 5 and 6 days following surgery. We set an arbitrary response criterion for demonstrating tactile allodynia on the operated side at ≦10 g. Only animals that passed this screening tests were used for drug testing. About 15% of animals operated were excluded on these grounds.

1.3. Pharmacological Treatments

Anesthetic reagents: ketamine (Fort Dodge, Fort Dodge, Iowa, USA) and xylazine (VMD, Arendonk, Belgium). Antibiotic: duplo-penicillin (Biochimie GmbH, Kundl, Austria). Drugs: Valproic acid (VPA), valpromide (VPD), valnoctic acid (VCA), valnoctamide (VCD), diisopropylacetic acid (DIA), diisopropylacetamide (DID), N-methyl-valpromide (MVPD), and gabapentin (GBP) were tested. VPD, VCD were gifts from Sanofi Labaz (France) VPA, and GBP were a gift from Teva Pharmaceuticals (Netanya, Israel). VCA, DIA, diisopropyl acetamide (DID) and MVPD were synthesized according to previously published procedures (Haj-Yehia and Bialer, 1989 & 1990: HAJ-YEHIA, A., & BIALER, M (1989). Structure-pharmacokinetic relationship in series of valpromide isomers with entiepileptic activity. Pharm. Res., 6, 683-689.

HAJ-YEHIA, A., & BIALER, M. (1990). Structure-pharmacokinetic relationship in series of short fatty acid amides that possess anticonvulsant activity. J. Pharm. Sci., 79, 719-724.). The products were identified and their structure was proved by nuclear magnetic resonance spectra and by elemental microanalysis. Each compound was suspended in 0.5% methylcellulose in double distilled water (MC, vehicle) and administered intraperitoneally (i.p.) in the doses noted below, in a uniform volume of 4ml/kg body weight. The following doses were tested: VPA 200, 250, 300 and 400 mg kg⁻¹; VPD 20, 60, 80 and 100 mg kg⁻¹; VCA 100, 200 and 300 mg kg⁻¹; VCD 20, 40, 60, 80 and 100 mg kg⁻¹; DIA 200 and 300 mg kg⁻¹; DID 20, 40, 80 and 90 mg kg⁻¹; MVPD 60, 120 mg kg⁻¹; and GBP 10, 30, 100 and 300 mg kg⁻¹.In addition, vehicle control injections were carried out using 4 ml kg⁻¹ MC.

Drug tests were conducted at 7, 14 and 21 days postoperative (dpo). In each rat two different doses of a particular drug and MC were assessed in a blind randomized crossover manner. Response to VFF probing was tested before for baseline (pre-) and then 30, 60, 120, 180 and 240 min after dosing. The individual who made the behavioral assessment was unaware of the drug/dose given. The first two doses of a drug were based on its potency (ED50) as an AED in the maximal electroshock (MES) test (Table 4). I.e., one dose was just below and the second was just above the MES ED50. Based on the results of the first experiment the next dosages were chosen in order to establish a scale of protection. VPAs first stage was 300 vs. 400 mg kg-1 vs. MC (n=8 rats tested per dose) and the second stage was 200 vs. 250 mg kg-1 vs. MC (n=8). VPD: 20 vs. 60 mg kg⁻¹vs. MC (n=8); 100 vs. 150 mg kg⁻¹ vs. MC (n=8); VPD 80 mg kg⁻¹ vs. VCA 300 mg kg⁻¹ vs. MC (n=9). VCA: 100 vs. 200 mg kg⁻¹ vs. MC (n=8). VCD: 40 vs. 80 mg kg⁻¹vs. MC (n=9); 20 vs. 60 mg kg⁻¹ vs. MC (n=8); 100 mg kg⁻¹ vs. MC (n=8). DIA: 200 vs. 300 mg kg⁻¹ vs. MC (n=8). DID 40 vs. 80 mg kg⁻¹vs. MC (n=7); 20 vs. 90 mg kg⁻¹ vs. MC (n=8). MVPD 60 vs. 120 mg kg⁻¹ vs. MC (n=9). GBP: 10 vs. 30 mg kg⁻¹ vs. MC (n=8); 100 vs. 300 mg kg⁻¹ vs. MC (n=9). A one-week washout period was used after each drug treatment. Five days after each drug administration the allodynic baseline threshold was re-evaluated, and 2 days later drugs effect were tested again.

1.5. Determination of the Median Effective Dose (ED₅₀)

To determine median effective dose (ED₅₀) as an estimate of the compounds' potency, we plotted a dose-response curve 60 min. post injection except for DID (and GBP) which were plotted at 120 min. These were the time points at which the largest fraction of rats tested first reached their maximal antiallodynic effect. Response was plotted as the percentage of animals tested at that time point that failed to respond to the 15 g VFF. Maximum possible response (100%) means that none of the rats tested responded to the 15 g VFF. ED₅₀ was the dose that yielded 50% of the maximum possible response. This value was linearly interpolated between the dose just above and just below the ED₅₀ value. These data were then subjected to probit analysis (Finney, 1971: FINNEY, D. J. (1971). Probit analysis. 3^(rd) ed. Cambridge, UK: Cambridge University Press). 95% confidence intervals (CI) of ED₅₀ were calculated. efficacy of a drug was defined as the percentage of animals tested that failed to respond to the 15 g VFF at the highest dose used, at which ED₅₀ was determined (60 or 120 min).

1.6. Analysis of Plasma Drug Concentration

For each of the drugs VPA and DID nine rats (320-350 g) underwent SNL surgery, and 28 days later were randomly divided into 3 groups of 3 rats per group. VPA (300 mg kg-1), and DID (40 mg kg-1) were administered in 4 ml kg-1 i.p. 0.5% MC, and 400 μl of blood were collected from the amputated tail tip at each of three time points after injection. Blood was withdrawn for group 1 at 15, 60 and 180 min after dosing; for group 2 at 30, 90 and 240 min after dosing and for group 3 at 45, 120 and 360 min after dosing. Plasma was immediately separated by centrifugation at 3000 g for 15 min and stored at −20° C. until analyzed.

Plasma levels of VPA and DID were determined by gas chromatography (GC). An HP5890 series II GC equipped with FID detector, HP7673 autosampler, for DID HP-5 capillary column (0.25 μ×15 m×0.25 mm) was used. The temperature program was as follows: injector temperature 250° C.; initial temperature, 60° C. for 3 min; gradient of 15° C. min-1 until 180° C.; hold 5 min. For each drug, plasma levels obtained from 3 rats at each time point were averaged. 25 μl of internal standard solution (50 mg L⁻¹ of VPD for the DID assay) and 200 μl of 0.1M NaOH were added to 50 μl of plasma. The mixture was vortexed, and 1 ml of chloroform was added. The phases were separated, and the chloroform was evaporated. The dry residue was redissolved in 50 μl of chloroform, and 1 μl was injected into the gas chromatograph. Calibration curves were prepared separately by spiking naive rat plasma samples with 1.56, 2.5, 3.12, 6.25, 12.5, 25.0, 37.5, 50.0, 75.0 and 100.0 mg L⁻¹ of DID. The limit of quantification (LOQ) of the method was 1.56 μg/ml, and the coefficient of variation (CV %) was <15% at all analyzed concentrations including LOQ.

For VPA determination a HP-FFAP capillary column (0.3 μm×25 m×0.2 mm) was used. The temperature program was as follows: injector temperature 280° C.; oven temperature, 135° C. 30 μl of internal standard solution (250 mg L-1 of 1-methyl-1 cyclohexane carboxylic acid, MCCA, in MeOH) and 125 μl of 5N Hydrochloric acid (HCl) were added to 250 μl of plasma. The mixture was vortexed, and 2 ml of chloroform was added. The phases were separated, and the 1 ml of NaOH was added. 200 μl of HCl 5N and 2 ml of chloroform were added to the aqueous phase. The organic layer was evaporated and dry residue was redissolved in 50 μl of chloroform, and 30 μl was injected into the gas chromatograph. Calibration curves were prepared separately by spiking naive rat plasma samples with 25.0, 50.0, 75.0, 100.0, 200.0, 300.0, 400.0, 500.0 and 600.0 mg L-1 of VPA. LOQ of the method was 25 mg L-1, and the coefficient of variation (CV %) was <15% at all analyzed concentrations including LOQ.

1.7. Pharmacokinetics (PK)

PK parameters were determined by non-compartmental analysis using the pharmacokinetic software package WinNonlin, version 4.0.1 (SCI Software, Lexington, Ky., U.S.A.; Yamaoka, et al., 1978 (YAMAOKA, K., NAKAGAWA, T., & UNO, T. (1978). Statistical moments in pharmacokinetics. J Pharmacokinet. Biopharm., 6, 547-558.); Gibaldi & Perrier, 1982 (GIBALDI, M., & PERRIER, D. (1982). Pharmacokinetics (2nd ed.). pp. 199-219 Marcel Dekker: New York.); Rowland & Tozer, 1995 (ROWLAND , M., & TOZER, T. (1995). Pharmacological Response. In: Clinical Pharamcokeintics. pp.340-365,) Baltimore: Williams & Wlkins.)). The terminal half-life (t ½) was calculated as 0.693/β, where β is the linear terminal slope of the concentration (C)-versus-time curve. The area under the C-versus-time curve (AUC) was calculated by trapezoidal rule with extrapolation to infinity. The mean residence time (MRT) was calculated from the quotient AUMC/AUC, where AUMC is the area under the concentration-time product versus time curve from zero to infinity. Total (apparent) clearance (CL/F) was calculated from the quotient of FDose/AUCm with F being the absolute bioavailablity following i.p. administration. The apparent volume of distribution (Vβ/F) was calculated from the quotient of CL and β. The peak plasma concentration (Cmax) and the time to reach Cmax (tmax) were determined empirically by visual inspection.

1. 8. Neurological Motor Dysfunction Tests

We confirmed that for VPA, VPD, VCD and DID the highest drug dose tested was not sufficient to cause neurological motor dysfunction or sedation as this might lead to false positive results in behavioral tests of sensory response (Yanez et al., 1990 (YANEZ, A., SABBE, M. B., STEVENS, C. W., & YAKSH, T. L. (1990). Interaction of midazolam and morphine in the spinal cord of the rat. Neuropharmacology 29, 359-364.); Jourdan et al., 1997 (JOURDAN, D., ARDID, D., BARDIN, M., NEUZERET, D., LANPHOUTHACOUL, L., & ESCHALIER, A. (1997). A new automated method of pain scoring in the formalin test in rats. Pain 71, 265-270.)). In n=6 normal rats, without nerve injury (body weight 250-350 g), changes in motor performance after VPA, VPD, VCD and DID administration were measured using an accelerating rotarod (Columbus Instruments, Columbus, Ohio, USA). The rotarod speed was increased from 10 to 30 rpm over a 120 sec. period, with the maximum time spent on the rod set at 120 s. For acclimation rats received two training trials (separated by 3-4 h) on two separate days prior to drug testing. On the day of testing, a baseline response was obtained, and rats were subsequently administered drug or vehicle. Motor performance (the time (sec.) to fall off the rotarod) was tested at the time (after dosing) when the ED₅₀ was determined i.e., 60 min (VPA, VPD, VCD) or 120 min (DID). In addition, we examined our rats individually for signs of motor dysfunction and sedation as assessed by posture and gate during spontaneous and induced movement, grooming, chewing, stepping reflex, and startle reflex evoked by tapping on the cage.

1.9. Statistical Analysis

Results are presented as the ED50 and 95% confidence interval (CI). For each drug and dose, attenuation of tactile allodynia (threshold measured in g) was measured. The average response of all time points after administration (30, 60, 120, 180 and 240 min), area under the response curve, was calculated and the pretreatment value was subtracted, per rat. These areas under the response curve values for every group of rats per dose were evaluated against vehicle treatment using the nonparametric Wilcoxon one tailed test (dose of drug tested vs. vehicle on the same treatment). The results for rotarod test (mean±standard deviation) were evaluated by the same statistical test (highest dose of drug tested vs. vehicle). A p value <0.05 was considered statistically significant.

Results

Pharmacodynamics (PD): Effect of Drugs on Tactile Allodynia

The drugs tested (shown in FIG. 6) showed significant, dose-dependent attenuation of tactile allodynia during the first few hours after i.p. injection. At the highest doses used, this antiallodynic drug effect was near maximal 30 min after injection with the exception of DID in which the degree of antiallodynia continued to increase after 30 min. The antiallodynic effect of the drugs began to decline 1-3 h post injection. For VPA and DID the maximal dose used was less than that required to produce signs of neurological motor deficits or sedation.

DIA

DIA was effective at a dose of 300 mg kg⁻¹, i.p. (FIG. 6), 25% of rats were regarded as protected at the highest dose.

DID

The lowest dose needed to significantly increase the allodynic threshold, when compared to vehicle, was 20 mg kg⁻¹, i.p. (FIG. 6) The response became larger in a dose-dependent manner at time points between 30 min and 120 min. The mean effective dose (ED₅₀) at 120 min after dosing was 58 mg kg⁻¹ with a 95% CI of 18-97 mg kg⁻¹. There was no response to 15 g or above VFF for 63% of rats at the highest dose tested.

VPA

VPA (used as reference, Figure not shown) decreased tactile allodynia in a dose-dependent manner. The lowest effective (i.p.) dose was 300 mg kg⁻¹. ED₅₀ 60 min after dosing was 269 mg kg⁻¹(95% CI of 227-310 mg kg⁻¹). At the highest dose tested (400 mg kg⁻¹, i.p.) 88% (7/8) of rats were relieved from tactile allodynia.

Pharmacokinetic (PK) Analysis The pharmacokinetics of VPA and DID was evaluated at low effective antiallodynic doses as found in the PD study, 300 and 40 mg kg⁻¹, respectively. The PK parameters was calculated using a non-compartmental approach (Yamaoka et al, 1978 (YAMAOKA, K., NAKAGAWA, T., & UNO, T. (1978). Statistical moments in pharmacokinetics. J Pharmacokinet. Biopharm., 6, 547-558.), Gibaldi and Perrier, 1982(GIBALDI, M., & PERRIER, D. (1982). Pharmacokinetics (2^(nd) ed.). pp. 199-219 Marcel Dekker: New York.) and are presented in Table 3. The antiallodynic effect of DID at this dose was associated with a minimal plasma concentrations of 7 mg L⁻¹, (FIG. 7). The antiallodynic effect of VPA at this dose was associated with a minimal plasma concentrations of 125 mg L⁻¹.

Rotarod Test

VPA, and DID, had no significant effect (p>0.05, n=6) on motor performance (rotarod test) at the highest doses tested (400, and 90 mg kg⁻¹, i.p., respectively), at 60 or 120 min after dosing when compared to vehicle treatment (96.8±23.7 and 103.8±22.3 seconds, vs. 118.0±2.3 respectively). TABLE 3 Table 3. Pharmacokinetic (PK) parameters of VPA and DID in the plasma after i.p. administration to SNL operated rats at doses of 300 and 40 mg kg⁻¹, respectively PK parameters VPA DID CL/F (L h⁻¹ kg⁻¹) 0.2 0.5 Vβ/F (L kg⁻¹) 1.2 1.2 t_(1/2) (h) 4.6 1.5 MRT (h) 5.8 2.4 Cmax (mg L⁻¹) 515 28 tmax (min) 30 15 F—Absolute bioavailability; CL/F—Clearance normalized by F; Vβ/F—Volume of distribution normalized by F; t_(1/2)—Half-life; MRT—Mean residence time; Cmax—Peak plasma concentration; tmax— Time to reach Cmax. Discussion

DID showed dose-related antiallodynic activity at doses that did not produce neurological motor deficit or sedation. Moreover, this compound proved to have much better antiallodynic potency than VPA.

The peak plasma concentration (Cmax) for VPA (Figure not shown), was obtained 30 min after dosing and its maximal antiallodynic effects were observed shortly afterwards, with a reasonable parallel between plasma concentration and antiallodynic activity also at subsequent time points. DID was exceptional in that its Cmax was obtained 15 min after dosing whilst its maximal antiallodynic effect was observed 120 min after dosing (FIG. 7).

Antiallodynic vs. Anticonvulsant Activity

The proven analgesic activity of some AEDs in animal models of neuropathic pain, and in placebo controlled clinical trials, naturally raises the suggestion that epilepsy and neuropathic pain share underlying neural mechanisms (McQuay et al., 1995 (MCQUAY, H., CARROLL, D., JADAD, A. R., WIFFEN, P. & MOORE, R. A., (1995). Anticonvulsant drugs for management of pain: a systematic review, Brit. Med. J. 311, 1047-1052.); Zakrzewska et al., 1997 (ZAKRZEWSKA, J. M., CHAUDHRY, Z., NURMIKKO, T. J, et al. (1997). Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain 73, 223-230.); Blom, 1962 (BLOM, S.(1962). Trigeminal neuralgia: its treatment with a new anticonvulsant drug. Lancet; 1, 839-840.); Rogawski & Loscher, 2004b (ROGAWSKI, M. A., & LOSCHER, W. (2004b). The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat. Med., 10, 685-692.)). The availability of ED50 data for a series of new anticonvulsant isomers and analogues of VPD (valpromide) provides an opportunity for testing this hypothesis. In fact, plotting the ED50 values for these and other AEDs for which corresponding data are available (carbamazepine-CBZ, felbamate-FBM, lamotrigine-LTG) and our series of VPA analogues did not yield a significant overall positive correlation (Table 4, FIG. 8). The rat-MES ED50 data presented in Table 4 were taken from previous studies and were obtained following oral administration (Bialer et al., 1994 (BIALER, M., HAJ-YEHIA, A., BADIR, K. & HADAD, S. (1994). Can we develop improved derivatives of valproic acid. Pharm. World Sci. 16, 2-6.)), in collaboration with the NIH anticonvulsant screening program (White et al., 2002 (WHITE. H. S., WOOHHEAD J. H., WILCOX, K. S., STABLES, J. P., KUPFERBERG, H. J. & WOLF, H. H. (2002). Discovery and preclinical development of antiepileptic drugs. in: Antiepileptic drugs. 5^(th) edit. Levy, R. H., Mattson, R. H., Meldrum, B. S., & Perucca, E, eds., pp. 36-48. Philadelphia: Lippincott Williams & Wilkins.)). TABLE 4 Activity of AEDs as anticonvulsants (MES test) and agents that suppress tactile allodynia in the SNL model of neuropathic pain in the rat. Relative brain access (blood-to-brain ratio) is also provided. MES-ED₅₀ SNL-ED₅₀ (mg kg⁻¹, (mg kg⁻¹, ED₅₀ Brain-to- Drug p.o.) i.p.) MES/SNL plasma ratio VPA 485^(a)   269 1.8 0.16^(c) VPD  32^(b)    61 0.5 0.84^(c) VCA NT >300 — NT VCD  29^(c)    52 0.6 1.0^(c) DIA NT >300 — NT DID 51    58 0.9 NT MVPD 65 >120 <0.54 NT GBP 14.8^(a)     34^(d) 0.43 0.85^(e) FBM 25.3^(a)  >600^(d) <0.04 0.64^(f) LTG 1.3^(a)  >100^(d) <0.01 0.4^(h) CBZ 5.4^(a)    >30^(c) <0.18 1.0^(i) ^(a)Data from White et al., 2002 ^(b)Data from Bialer et al., 1994 ^(c)Data from Blotnik et al., 1996 ^(d)Data from Hunter et al., 1997 ^(e)Data from Vajda, 2002 ^(f)Data from Pellock et al., 2002 ^(h)Data from Walker et al., 2000 ^(i)Data from Spina, 2002

WHITE. H. S., WOOHHEAD J. H., WILCOX, K. S., STABLES, J. P., KUPFERBERG, H. J. & WOLF, H. H. (2002). Discovery and preclinical development of antiepileptic drugs. in: Antiepileptic drugs. 5 ^(th) edit. Levy, R. H., Mattson, R. H., Meldrum, B. S., & Perucca, E, eds., pp. 36-48. Philadelphia: Lippincott Williams & Wilkins.

BIALER, M., HAJ-YEHIA, A., BADIR, K. & HADAD, S. (1994). Can we develop improved derivatives of valproic acid. Pharm. World Sci 16, 2-6.

BLOTNIK, S., BERGMAN, F., & BIALER, M,. (1996). Disposition of valpromide, valproic acid and valnoctamide in the brain, liver, plasma and urine of rats. Drug Metab. Disposit., 24, 560-564.

HUNTER, J. C., GOGAS, K. R., HEDLEY, L. R., JACOBSON, L. O., KASSOTAKIS, L., TOMPSON, J., & FONTANA, D. J. (1997). The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain. Eur. J. Pharmacol., 324,153-160.

VAJDA, F. J. E. (2002). Gabapentin-Chemistry, biotarnsoformation, pharmacokinetics and interactions. in: Antiepileptic drugs. 5^(th) edit. Levy, R. H., Mattson, R. H., Meldrum, B. S., & Perucca, E,. eds., pp. 335-339. Philadelphia: Lippincott Williams & Wilkins.

PELLOCK, J. M., PERHACH, J. L., & SOFIA, R. D. (2002). Felbamate. in: Antiepileptic drugs. 5th edit. Levy, R. H., Mattson, R. H., Meldrum, B. S., & Perucca, E,. eds. pp. 301-18 Philadelphia: Lippincott Williams & Wilkins.

WALKER, M. C., TONG, X., PERRY, H., ALAVIJEH, M. S., & PATSALOS, P. N. (2000). Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine. Br. J. Pharmacol. 130, 242-248.

SPINA E. (2002). Carbamazepine-Chemistry, biotarnsoformation, pharmacokinetics and interactions. in: Antiepileptic drugs. 5^(th) edit. Levy, R. H., Mattson, R. H., Meldrum, B. S., & Perucca, E,. eds., pp. 232-246. Philadelphia: Lippincott Williams & Wilkins.

MES, maximal electro-shock; ED₅₀, median effective dose; SNL, spinal nerve ligation; NE, no effect; NT, not tested; CBZ, carbamazepine; FBM, felbamate; LTG, lamotrigine.

In a different study several CNS-active tetramethylcylcopropyl amide analogues of VPA have been assessed for their antiallodynic activity, utilizing the SNL model (data not shown). All tested compounds showed dose-related reversal of tactile allodynia. 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) and its primary amide 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD) were the only agents to exhibit antiallodynic effect without any anticonvulsant activity in the rat-MES test.

The results show that the compounds (TMCD, M-TMCD, VCD, DID, DIA, PID) are effective for treating neuropathic pain. The compounds were highly effective compared to valproic acid as evident by the lower ED₅₀ values (compared to valproic acid). The results show that M-TMCD and VCD are more preferred compounds.

While this invention has been shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that many alternatives, modifications and variations may be made thereto without departing from the spirit and scope of the invention. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. 

1. A method for treating a disease or condition selected from: neuropathic pain, migraine, and neuronal degeneration, in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula [A]:

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein (i) X is selected from OH and NR¹R²; (ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; (iii) n is 0 or 1; and (iv) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R^(5,) R⁶ are independently selected from H and C₁-C₆ alkyl; or (b) one of R³ and R^(4,) together with one of R⁵ and R⁶, form a cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected from H and C₁-C₆ alkyl, including pharmaceutically acceptable salts, hydrates and solvates of the compound of formula [A], with the exclusion of the following compounds in racemic and stereoisomeric forms for treating migraine: propylisopropyl acetic acid, propylisopropyl acetamide, valnoctamide, valnoctic acid, diisopropyl acetamide and diisopropyl acetic acid.
 2. A method for treating a psychiatric disorder in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula [A] as defined in claim 1, with the exclusion of compounds of formula II:

wherein R¹ and R² are independently selected from H and C₁-C₆ alkyl.
 3. A method according to claim 1 for treating a disease or condition selected from: neuropathic pain, migraine, and neuronal degeneration, in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound of formula I

as racemic mixtures or as individual stereoisomers or mixtures of racemic and stereoisomers, wherein (i) X is selected from OH and NR¹R²; (ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and (iii) (a) R³, R⁴ are independently selected from H and C₁-C₆ alkyl; R⁵, R⁶ are independently selected from H and C₁-C₆ alkyl; or (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected from H and C₁-C₆ alkyl, including pharmaceutically acceptable salts, hydrates and solvates of the compound of formula [I], with the exclusion of the following compounds in racemic and stereoisomeric forms for treating migraine: valnoctamide, valnoctic acid, diisopropyl acetamide and diisopropyl acetic acid.
 4. The method according to claim 1 wherein said C₁,-C₆ alkyl group is a straight or a branched alkyl group.
 5. The method according to claim 3 wherein the total number of carbon atoms of R³, R⁴, R⁵ and R⁶ in a compound of formula I is two.
 6. The method according to claim 3 wherein (i) X is selected from OH and NR¹R²; (ii) R¹, R² are independently selected from H and C₁-C₆ alkyl; and (iii) (a) R³, R⁴ are independently selected from H, methyl and ethyl; R⁵, R⁶ are independently selected from H, methyl and ethyl; or (b) one of R³ and R⁴, together with one of R⁵ and R⁶, form a cyclopropyl ring, and the other of R³, R⁴, R⁵ and R⁶ is selected from H, methyl and ethyl.
 7. The method according to claim 3 wherein X is selected from OH and NR¹R²; R¹, R² are independently selected from H and C₁-C₆ alkyl; and one of R³ and R⁴, together with one of R⁵ and R⁶, form a cyclopropyl ring and the other of R³, R⁴, R⁵ and R⁶ is a methyl.
 8. The method according to claim 7 having the structural formula II

wherein R¹ and R² are independently selected from H and C₁-C₆ alkyl.
 9. The method according to claim 7 wherein at least one of R¹ and R² is H and the other of R¹ and R² is a C₁-C₆ alkyl.
 10. The method according to claim 7 wherein said C₁-C₆ alkyl is a methyl.
 11. The method according to claim 7 wherein said compound is N-Methyl-2,2,3,3 -tetramethylcyclopropanecarboxamide.
 12. The method according to claim 7 wherein said compound is 2,2,3,3-tetramethylcyclopropanecarboxamide.
 13. The method according to claim 3 wherein said compound is 2-ethyl-3-methyl-pentanoic acid amide, as racemic mixture or as individual stereoisomers or mixtures of racemic and stereoisomers, including pharmaceutically acceptable salts, hydrates and solvates thereof, for the treatment of neuropathic pain and neuronal degeneration.
 14. The method according to claim 3 wherein said compound is 2-ethyl-3-methyl-pentanoic acid, as racemic mixture or as individual stereoisomers or mixtures of racemic and stereoisomers, including pharmaceutically acceptable salts, hydrates and solvates thereof, for the treatment of neuropathic pain and neuronal degeneration.
 15. The method according to claim 7 wherein said compound is 2,2,3,3-tetramethylcyclopropanecarboxylic acid.
 16. The method according to claim 1 for treating neuropathic pain or neuronal degeneration, wherein said compound is propyl isopropylacetamide (PID) as racemic mixture or as individual 2R and 2S stereoisomers or mixtures of racemic and stereoisomers, including pharmaceutically acceptable salts, hydrates and solvates thereof.
 17. The method according to claim 1 wherein said compound is diisopropylacetamide (DID).
 18. The method according to claim 1 wherein said compound is diisopropylacetic acid (DIA).
 19. The method according to claim 1 wherein said disease or condition is a neuropathic pain.
 20. The method according to claim 1 wherein the route of administration of said compound is selected from oral, parenteral, topical, transdermal, mucosal, rectal and buccal administration.
 21. The method according to claim 1 wherein the route of administration of said compound is selected from oral and parenteral administration.
 22. The method according to claim 21 wherein said parenteral route of administration is selected from intravenous, intramuscular, intraperitoneal and subcutaneous administration.
 23. The method of claim 1 wherein said mammal is a human. 